Abstract
While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Our previous results show that CD40L-overexpressing CAR T cells mobilize endogenous immune effectors, resulting in improved antitumor immunity. However, the cell populations required for this protective effect remain to be identified. Here we show, by analyzing Batf3-/- mice lacking the CD103+ conventional dendritic cell type 1 (cDC1) subpopulation important for antigen cross-presentation, that CD40L-overexpressing CAR T cells elicit an impaired antitumor response in the absence of cDC1s. We further find that CD40L-overexpressing CAR T cells stimulate tumor-resident CD11b-CD103- double-negative (DN) cDCs to proliferate and differentiate into cDC1s in wild-type mice. Finally, re-challenge experiments show that endogenous CD8+ T cells are required for protective antitumor memory in this setting. Our findings thus demonstrate the stimulatory effect of CD40L-overexpressing CAR T cells on innate and adaptive immune cells, and provide a rationale for using CD40L-overexpressing CAR T cells to improve immunotherapy responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptive Immunity
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Animals
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Antigen Presentation
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Antigens, CD / genetics
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Antigens, CD / immunology
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Basic-Leucine Zipper Transcription Factors / deficiency
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / immunology
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CD11b Antigen / deficiency
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CD11b Antigen / genetics
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CD11b Antigen / immunology
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CD40 Ligand / genetics*
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CD40 Ligand / immunology
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Female
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Gene Expression
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Immunity, Innate
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Immunophenotyping
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Immunotherapy, Adoptive / methods*
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Integrin alpha Chains / deficiency
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Integrin alpha Chains / genetics
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Integrin alpha Chains / immunology
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / immunology
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Lymphoma, B-Cell / pathology
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Lymphoma, B-Cell / therapy*
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Neoplasm Transplantation
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Receptors, Chimeric Antigen / genetics*
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Receptors, Chimeric Antigen / immunology
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Repressor Proteins / deficiency
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Repressor Proteins / genetics
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Repressor Proteins / immunology
Substances
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Antigens, CD
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Basic-Leucine Zipper Transcription Factors
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CD11b Antigen
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Integrin alpha Chains
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Itgam protein, mouse
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Receptors, Chimeric Antigen
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Repressor Proteins
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SNFT protein, mouse
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alpha E integrins
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CD40 Ligand